Pulmonary hypoplasia continues to be the most significant limiting factor for the survival of neonates with congenital diaphragmatic hernia (CDH), renal dysplasia or other conditions associated with lung underdevelopment. Although there is some degree of lung growth and remodeling soon after birth, those changes occur over a period of time that exceeds the current limitations of supportive treatment, which includes mechanical ventilation, high-frequency ventilation, and extracorporeal membrane oxygenation (ECMO). In addition, some studies suggest that mechanical ventilation of the hypoplastic lungs actually contributes to an impairment of subsequent alveolar development. As a result, all patients with severe forms of lung hypoplasia are still unsalvageable.
There is evidence that lung liquid is critical to lung growth in the fetus and that fetal lung liquid volume must be maintained for normal lung growth to occur. It is well known, through several controlled studies as well as experiments of nature, that complete occlusion of the fetal airway markedly accelerates pulmonary growth, sometimes even beyond normal limits, both in otherwise normal and in hypoplastic lungs. Fetal tracheal occlusion, while preserving the normal maturation process, also reverses pulmonary hypoplasia associated with experimental CDH and produces lungs that are more compliant and more efficient at gas exchange.
Although the specific mechanisms responsible for pulmonary growth or hyperplasia after fetal airway occlusion are not known, there is strong evidence that increased intratracheal (ITP) and intrapulmonary (IPP) pressure plays a major role in the process. In normal fetal lambs, maximal lung growth occurs between 112 and 124 days' gestation, a period which coincides with significant elevation in ITP. Animals submitted to fetal tracheal ligation have been found to have ITP of 6-7 mm Hg, well above the 1.8-2.0 mm Hg values reported in normal fetal lambs of similar gestational age in utero. Those findings are in accordance with the observations of Alcorn et al., who reported ITP of 6.4 mm Hg in fetal lambs submitted to tracheal ligation (J Anat 123:649-660 (1977)). Conversely, chronic drainage of fetal lung liquid and deceased ITP leads to pulmonary hypoplasia. This body of data suggests that fetal tracheal ligation reverses pulmonary hypoplasia by enhancing normal mechanisms of fetal lung growth, which in turn seems to be dependent on positive ITP/IPP.
Fetal surgery, however, is still faced with significant limitations, mainly with regard to the control of premature labor, and has met with limited success so far. An additional problem associated with human fetal surgery at this time is the fact that the severity and prognosis of pulmonary hypoplasia associated with CDH, for instance, cannot be accurately predicted prenatally, rendering the current indications for fetal surgery in this anomaly dubious. Yet another question to be answered before fetal intervention is indicated is how the lungs that underwent accelerated growth because of tracheal occlusion will function in the mid- to long term. Since bronchial development is complete by 16 weeks gestation, which is long before the time when fetal manipulation is feasible with the technology currently available, those lungs may be so-called "polyalveolar", functioning well at birth, but perhaps not as well, later in life.
In addition, it is known that many other cell types respond to stretch stimulus from increased pressure and/or volume. Tissue or organ hyperplasia in response to increased pressure and/or volume has been observed in the epidermis, the heart, and the digestive and urinary tracts as well.
Accordingly, there exists a need for a therapeutic tool that can actively promote pulmonary as well as other tissue and organ growth, particularly postnatally without the need for fetal intervention.